SO-31 Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An expanded dataset
Authors: E. Garralda, D. Hong, R. Xu, J. Deeken, A. Italiano, T. Liu, A. Ferrandiz, J. Patel, D. Lee, H. Chung, I. Kinoshita, J. Berlin, T. André, D. Oh, S. Leyvraz, M. Miguel, Y. Liu, R. Norenberg, M. Fellous, C. Mussi, A. Drilon, L. Shen
Journal: Annals of Oncology (2022)

Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions are oncogenic drivers in various tumour types. Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved for use in adult and paediatric patients with TRK fusion cancer, demonstrating an objective response rate (ORR) of 41% across 18 patients with gastrointestinal (GI) cancer (Boni et al, WCGI 2021). We report an updated analysis from an expanded dataset of patients with TRK fusion GI cancer with longer follow-up. Patients with TRK fusion GI cancer treated with larotrectinib in the phase II clinical trial NAVIGATE (NCT02576431) were included in this analysis. Responses were investigator-assessed using RECIST v1.1. Data cut-off was 20 July 2021. As of data cut-off, 34 patients with metastatic TRK fusion GI cancer were enrolled. Median age was 63.5 years (range 32–90). The tumour types included were colorectal (CRC; n=19), pancreatic (n=6), cholangiocarcinoma (n=4), appendiceal (n=1), duodenal (n=1), gastric (n=1), hepatocellular carcinoma (n=1) and oesophageal (n=1). Among the patients with CRC, 10 were microsatellite instability high (MSI-H), seven were MSI-H not detected (including stable) and two were unknown. Overall, 32%, 35% and 18% of patients had received 1, 2, or ≥3 prior lines of systemic therapy, respectively. ORR in the 33 evaluable patients was 33% (95% confidence interval [CI] 18–52): one complete response (CR; 3%), 10 partial responses (PR; three pending confirmation [30%]), 15 stable disease (SD; 45%), four progressive disease (PD; 12%) and three not determined (ND; 9%). Median time to response was 1.9 months (range 1.7–5.0). Median duration of response (DoR) was 7.3 months (95% CI 3.5–27.3); median follow-up was 26.4 months. Median progression-free survival (PFS) was 5.4 months (95% CI 2.7–9.0); median follow-up was 5.4 months. Median overall survival (OS) was 12.5 months (95% CI 6.1–33.4); median follow-up was 7.7 months. In the 19 patients with CRC, ORR was 47% (95% CI 24–71): one CR (5%), eight PR (three pending confirmation [42%]), eight SD (42%), one PD (5%) and one ND (5%). Of the nine responders, six were MSI-H. The median DoR was not reliably estimable, but the 12-month rate was 67% (95% CI 29–100); median follow-up was 17.8 months. Median PFS was 5.5 months (95% CI 2.7–not estimable); median follow-up was 5.6 months. Median OS was 12.5 months (95% CI 6.1–36.5); median follow-up was 7.8 months. Treatment duration for all GI patients ranged from 0.2+ to 32.2+ months. At data cut-off, 14 patients had progressed; four continued treatment post-progression for ≥4 weeks. Treatment-related adverse events (TRAEs) occurred in 65% of patients (27% were Grade [G]1, 21% G2, 12% G3 and 6% G4). No patients discontinued treatment due to TRAEs. In this expanded dataset with longer follow-up, larotrectinib continues to demonstrate rapid, durable responses, extended survival and a favourable safety profile in patients with TRK fusion GI cancer, particularly in those with CRC. These results highlight the importance of identifying NTRK gene fusions in patients with GI cancer, particularly in those with MSI-H CRC.